Abdominal aortic aneurysm (AAA) is a devastating disease that can cause aortic rupture and instantaneous death. AAAs affect approximately 10% of population over the age of 50 but most patients remain undiagnosed. The cost associated with surgical repair and duration of hospital stay for treating AAAs is significant and therefore there is a need for developing non-surgical treatments. This application proposes the investigation of Nuclear Factor-kB (NF-kB)/RelA signaling in aortic fibroblast in the angiotensin I (ang II) infusion model of AAAs. Insights from these studies may lead to development of therapeutics that target signaling in aortic fibroblasts to confer protection from AAAs and aortic rupture. Ang II infusion into mice leads to macrophage accumulation and fibroblast proliferation in the adventitial layer of the abdominal aorta, an early event in AAA formation. Although macrophage accumulation is crucial to AAA development, the role of fibroblast in AAA pathogenesis remains unknown. Preliminary results suggest that NF-kB/RelA-signaling in aortic fibroblasts protects from AAA and aortic rupture possibly by promoting the differentiation of fibroblast to myofibroblast. Myofibroblasts are known to remodel extracellular matrix (ECM) and to provide structural stability to the organ. Specific Aim 1 will test the hypothesis that fibroblat-RelA mediates myofibroblast formation and protection from AAA. This hypothesis will be tested using a novel, fibroblast-specific RelA-deficient mouse model that was generated in our lab. In addition, human aortic fibroblasts will be used to study NF-kB/RelA-signaling cascades that lead to myofibroblast formation and to determine whether NADPH oxidase 4 (Nox4) expression is downstream of RelA in the differentiation process. Specific Aim 2 will explore the hypothesis in vivo that RelA signaling via Nox4 is necessary for aortic fibroblast to myofibroblast differentiatin and for protection of aortic wall from aneurysmal expansion. This hypothesis will be tested in wild-type mice treated with the Nox4 inhibitor GKT137831 and in Nox4 deficient transgenics. These studies will enhance our limited understanding of the cellular and molecular mechanisms involved in AAAs and should stimulate the development of new therapeutic strategies that promote myofibroblasts in the aortic wall. In addition to the research plan, the complete training proposed in this application, which includes didactic learning, mentorship and clinical work will promote the development of the applicant toward a vigorous career in cardiovascular research as a physician-scientist.